The present invention relates to an iontophoresis device suitable for the percutaneous administration and the application through the mucous membranes and in particular to an iontophoresis device activated upon the practical use.
Recently, there have been developed a variety of dosage forms in the field of pharmaceutical preparations for external use and the development of dosage forms has gradually become a matter of great concern. The reason for this is as follows: The administration of a drug, which may have a local or systemic pharmacological action, through the skin or the mucous membranes has many advantages. For instance, the sustained-release effect of the drug can be expected; such administration is not greatly influenced by the metabolism due to the first-pass effect in the liver unlike the oral administration and permits the effective use of the drug; and drugs accompanied by, for instance, liver disorders can relatively safely be administered to a patient.
However the normal skin naturally has a protective effect against external stimulations and this makes the absorption and penetration of a drug through the skin relatively difficult. For this reason, in the existing circumstances, a drug is not absorbed in an amount sufficient for ensuring a satisfactory effect even if the drug is administered to a patient in a dosage form for external use. Moreover, in the administration method, which makes use of absorption routes through biological membranes other than the skin, such as mouth, rectum, oral cavity and nose as well as the sublingual route, it is difficult to penetrate into or transmit through the related biological membranes depending on the kinds of drugs and therefore, there have been known a large number of drugs having low bioavailability. Accordingly, there has been desired for the development of an absorption-promoting method, which can sufficiently enhance the permeability, penetrability and absorbency of a drug against the skin and other biological membranes, can ensure a sufficient pharmacological efficacy of the drug and is substantially free of, for instance, its local and systemic toxicity and is highly useful and safe.
As such absorption-promoting methods, there have recently been known chemically promoting methods, which make use of absorption-promoting agents, and physically promoting methods in which iontophoresis or phonophoresis techniques are employed. Among these, the iontophoresis technique has unexpectedly attracted special interest recently and has been expected as an administration method, which can solve the foregoing problems.
The iontophoresis technique is a method for the administration of a drug by applying an electric voltage to the skin or a mucous membrane to electrically induce the migration of an ionic drug and to thus administrate the drug through the skin or a mucous membrane. In general, an iontophoresis device is provided with a pair of electrode for iontophoresis, i.e., an anode and a cathode and the device is so designed that these electrodes are arranged on or attached to the skin at a predetermined distance apart from one another and an electric current generated by a current generator is guided to these electrodes to thus effect treatments of patients.
Moreover, this iontophoresis device has a structure which comprises a combination of these electrodes and a layer, which stores a drug therein, and avariety of additives for maintaining the drug efficacy are, if necessary, enclosed in the layer in addition to a predetermined amount of the effective component in order to keep a desired blood concentration in the body over a long period of time.
It has been a recent tendency to study the administration, by the iontophoresis, of polypeptide type drugs, which should be administered in a time control or intermittent type mode. Originally, the physiologically active peptides and proteins are decomposed by the digestive juice in the gastrointestinal tracts and simultaneously hydrolyzed by the hydrolases present on the wall of the digestive tract. For this reason, it is difficult to improve the absorption efficiency of these drugs and it is the leading mainstream in the medical field to administer the drugs not orally, but through injection. However, the administration through injection would give a heavy physical burden to a patient and is not always a treating method of a high compliance. Contrary to this, the iontophoresis permits the establishment of any absorption pattern by strictly controlling the electrical charging time and is an effective percutaneous absorption system which can realize an effective drug treatment, while taking into consideration the circadian rhythm, in particular, in the treatment in which an endogenous compound is supplemented. Therefore, if an iontophoresis device that permits the administration of drugs by a patient per se can be developed, it would be possibly to open the way for the home treatment.
According to the conventional studies, there have been proposed a large number of techniques relating to drug supports, which takes, into consideration, the instability of polypeptide type drugs to water and the high adsorbing ability thereof. For instance, Japanese Un-Examined Patent Publication Nos. Hei 2-218375 and Hei 2-206473 disclose drug supports capable of being electrically communicated with an electrode on the drug-administration side and capable of being brought into contact with the skin. As the drug supports of this type, there have been known, for instance, those constituted by organic members and those constituted by inorganic members. In addition, as methods for applying a drug to the drug support, there have been used, for instance, methods for coating the support with a drug or impregnating the support with a drug; or methods for applying a drug by drying or half-drying.
In these methods, however, it has been believed that drugs such as physiologically active peptides or proteins may be adsorbed on the drug support and accordingly, the rate of transdermal absorption of the drug is reduced. For this reason, there have also been proposed many techniques for solving the problem of the adsorption of drugs on the drug support. For instance, Japanese Un-Examined Patent Publication No. Hei 6-16535 discloses a technique comprising the step of coating aporousorcapillarystructuremadeof anon-conductivematerial with ahigh molecular weight protein such as bovine serum albumin, human serum albumin or gelatin. Moreover, Japanese Un-Examined Patent Publication No. Hei 8-98894 discloses an interface for the iontophoresis device in which a coating layer of an ionic surfactant is formed on a drug support material. In addition, Japanese Un-Examined Patent Publication No. Hei 9-56827 discloses an interface for the iontophoresis device in which a physiologically active peptide is deposited on or applied to a thin film having an average pore size ranging from 0.1 to 15 xcexcm, a porosity ranging from 65 to 90% and a low protein adsorptivity. Moreover, Japanese Un-Examined Patent Publication No. Hei 9-77658 discloses a technique comprising the step of applying a drug onto a hydrophobic area formed on a part of a hydrophilic film to thus give a transdermally absorbable pharmaceutical preparation.
In the conventional techniques, however, the drug support is in an exposed state and therefore, the drug is lost by any physical contact and through adsorption on the skin of a patient by any accidental touch with hands upon the application thereof, even if the drug in the dried condition is supported on the drug support. Moreover, when a drug support, which makes use of a porous hydrophilic film, is used and when a drug solution is supplied to the drug support or a drug included in the drug supportinthedriedconditionisre-dissolved, thedrugsolution diffuses from the center of the drug support to the periphery thereof due to the capillary phenomenon. Therefore, such a drug support suffers from a problem in that the drug solution moves towards an adhesive layer (for fitting the support to the skin) disposed at the periphery of the support and the amount of the drug to be used for the treatment is reduced.
On the other hand, when it is intended to incorporate, into a drug support, a drug having a high adsorbing ability and unstable to moisture, care should be taken not to lose a drug solution due to the movement thereof to other members during the term extending from the application of the drug to the completion of the drying. Otherwise the drug would be lost. It is necessary to prevent any movement of the drug towards other members during storing the drug support, or any movement of the drug towards other members during assemblage (or preparation) of a pharmaceutical preparation dissolved immediately before the practical use and during usage (during treatment), for the same reason.
In addition, it is sometimes observed that when the drug support is joined to the drug-dissolving portion, the air, which penetrates into the joint plane, would inhibit uniform dissolution of the drug and accordingly, the application of the device never ensures any sufficient drug efficacy. This would likewise be considered to be a drug loss in a wide sense and such insufficient dissolution of the drug present in the drug support would inhibit the effective use of the drug. Moreover, the electrical charging of the device is non-uniform due to the air penetration and there is sometimes observed skin stimulations upon practical use. The inventors of this invention were the first research workers to experience such a problem during studying and developing an iontophoresis device and there has never been known any prior art which refers to this problem.
Accordingly, it is an object of the present invention to provide an iontophoresis device suitable for effective use of a drug incorporated into a drug support as well as a drug unit.
The foregoing object of the invention can be accomplished by providing an iontophoresis device which comprises a drug-dissolving portion having a drug-activation function and a drug support subjected to a treatment for inhibiting any drug diffusion and/or a treatment for exhausting air and removably connected to the drug dissolving portion.
Thus, if the drug support is subjected to a drug diffusion-inhibitory treatment, the dissolved drug does not migrate to other members and the drug may efficiently be used. In addition, if the drug support is subjected to a treatment for exhausting any air, any air present is exhausted when the drug-dissolving portion is joined to the drug support and the drug is uniformly dissolved. Therefore, the drug can likewise efficiently be used in this case.
In this respect, the drug support can be subjected to a drug diffusion-inhibitory treatment by disposing a resin part or a thermally compressible portion at the periphery of the drug support. In addition, the air-exhausting treatment may comprise the step of forming an air vent hole at the periphery of the drug support.
Moreover, the drug support prior to the practical use is provided in the form housed in a drug unit. This drug unit is provided with members such as a drug support for accommodating a drug, a cover placed on one side of the drug support, a cover placed on the other side of the support and an adhesive for removably fixing the both covers to the drug support. These covers also serves as members for protecting the drug support and thus examples thereof usable herein are liners and caps or lids covering or put on the drug support. In addition, if necessary, the cover may be subjected to a drug adsorption-inhibitory processing or a drying agent for maintaining drugs in the dry condition may be positioned within the drug unit. Such a construction of the drug unit permits the protection of the drug support from any touch with hands and/or any physical contact immediately before the practical use. In addition, the construction also prevents any transfer of the drug to other members and can maintain the drug in its dry state. Thus, the drug support allows the effective use of the drug accommodated therein.